product name AZD8330
Description: AZD8330, also known as ARRY704 and ARRY424704, is a novel, selective, non-ATP competitive MEK 1/2 inhibitor with IC50 of 7 nM. It is an orally active MEK inhibitor with potential antineoplastic activity. MEK inhibitor AZD8330 specifically inhibits mitogen-activated protein kinase kinase 1 (MEK or MAP/ERK kinase1), resulting in inhibition of growth factor-mediated cell signaling and tumor cell proliferation.
References: Clin Cancer Res. 2007 Mar 1;13(5):1576-83.
461.23
Formula
C16H17FIN3O4
CAS No.
869357-68-6
Storage
-20℃ for 3 years in powder form
-80℃ for 2 years in solvent
Solubility (In vitro)
DMSO: 92 mg/mL (199.5 mM)
Water: <1 mg/mL
Ethanol: 92 mg/mL (199.5 mM)
Solubility (In vivo)
0.5% hydroxyethyl cellulose+0.1% Tween 80: 30mg/mL
Synonyms
ARRY704
other peoduct :
| In Vitro |
In vitro activity: AZD8330 potently and strongly inhibits MEK 1/2. AZD8330 has no inhibitory activity against over 200 other kinases including at concentrations up to 10 μM. AZD8330 demonstrates sub-nanomolar potency in mechanistic (pERK) and low to sub-nanomolar potency in functional (proliferation) assays in MEK 1/2 inhibitor sensitive cell lines. Kinase Assay: NH2-terminal hexahistidine tagged, constitutively active MEK1 (S218D, S222D ΔR4F) is expressed in baculovirus-infected Hi5 insect cells and purified by immobilized metal affinity chromatography, ion exchange, and gel filtration. The activity of MEK1 is assessed by measuring the incorporation of [γ- 33P]phosphate from [γ-33P]ATP onto ERK2. The assay is carried out in a 96-well polypropylene plate with an incubation mixture (100 μL) composed of 25 mM HEPES (pH 7.4), 10 mM MgCl2, 5 mM β-glycerolphosphate, 100 μM sodium orthovanadate, 5 mM DTT, 5 nM MEK1, 1 μM ERK2, and 0 to 80 nM AZD8330 (final concentration of 1% DMSO). The reactions are initiated by the addition of 10 μM ATP (with 0.5 μC k[γ-33P]ATP/well) and incubated at room temperature for 45 min. An equal volume of 25% trichloracetic acid is added to stop the reaction and precipitate the proteins. Precipitated proteins are trapped onto glass fiber B filter plates, excess labeled ATP is washed off with 0.5% phosphoric acid, and radioactivity is counted in a liquid scintillation counter. ATP dependence is determined by varying the amount of ATP in the reaction mixture. The data are globally fitted. Cell Assay: Malme-3M melanoma cells are plated in 96-wells and treated with various concentrations of AZD8330 for 1 hour at 37 °C. The cells are fixed, permeabilized, and incubated with an anti-phospho-ERK antibody and an anti-ERK 1/2 antibody. Plates are washed and fluorescently-labeled secondary antibodies are added. Plates are analyzed on a LICOR fluorescence imager. The pERK signal is normalized to the total ERK signal. |
|---|---|
| In Vivo | In a Calu-6 rat xenograft pharmacokinetic/pharmacodynamic (PK/PD) model a single, 1.25 mg/kg oral dose of AZD8330 inhibits ERK phosphorylation by > 90% for between 4 and 8 hours. Doses as low as 0.4 mg/kg once daily are sufficient for > 80% tumor growth inhibition in the Calu-6 nude rat xenograft model. In the Calu-6 model, AZD8330 inhibits tumor growth in a dose-dependent fashion, at 0.3 mg/kg and 1.0 mg/kg once daily |
| Animal model | Female nude rats with Calu-6 cells, nude rats with SW620 cells |
| Formulation & Dosage | Dissolved in 0.5% HPMC-0.1% Tween; 0.3, 1 mg/kg; Oral gavage |
| References | Clin Cancer Res. 2007 Mar 1;13(5):1576-83. |
